This project is designed to further characterize and evaluate the toxic effects on the brain resulting from exposure to managenese (Mn), an essential heavy metal and potential environmental pollutant, which produces clinical signs resembling Parkinson's Disease. While Mn is reported to reduce levels of dopamine (DA) in extrapyramidal structures of the brain, the significance of these results, and the involvement of other brain areas and neurochemicals is less well understood. This project will emphasize a more widespread consideration of factors which influence DA neurotransimission and will also compare different forms and routes of exposure. To this end, mice will receive toxic concentrations of Mn and DA turnover and pre-and post-synaptic DA receptors will be evaluated in several regions of the brain. These will be measured by HPLC determination of the DA metabolite DOPAC, the pharmacological response to low doses of apomorphine, and ligand binding (to D1 and D2 receptors), respectively. Secondly, possible neuro-endocrine toxicity will be investigated by exposing rats to Mn and determining changes in DA content and turnover in the hypothalamic-median eminence axis and correlating any observed effects with levels of plasma prolactin, a pituitary function regulated by DA. Thirdly, mice will be exposed to the fuel-additive MMT via inhalation in order to more closely simulate expected environmental exposure, and the toxicity by this route will be compared with previous results obtained from oral or parenteral exposure to MMT or Mn3O4. In all of the above cases, tissue levels of Mn will be measured (by AA spectrometry) to ensure that the severity of the toxicity co-varies with Mn exposure. In addition, the influence of Mn toxicity on other neurotransmitters which have a regulatory influence on DAergic activity, namely GABA, Substance P and enkephalins, will be measured by examining possible Mn-induced alterations in content and receptor binding in different parts of the brain.